The present invention relates to novel compositions of matter. More particularly, the present invention relates to stable, water miscible pharmaceutical compositions. Most particularly, the present invention relates to stable, rapidly water miscible compositions of PGE-type compounds.
The prostaglandins are a family of 20 carbon atom fatty acids, being structural derivatives of prostanoic acid, which exhibit useful activity in a wide variety of biological systems. Accordingly, such prostaglandins represent useful pharmacological agents in the treatment and prevention of a wide variety of disease conditions. Prostanoic acid has the carbon atom numbering and structure as shown by formula I, below. A trivial system of nomenclature has been devised, which classifies the prostaglandins according to the substituents on the cyclopentane ring. See, N. A. Nelson, Journal of Medicinal Chemistry, 17:911 (1974). The terms "PGE-type compounds" or "E-type prostaglandins" are used to describe structural analogs of the prostaglandins having the substituents around the cyclopentane ring as shown in formula II, below. The formula II compound named is PGE.sub.2. For a fuller discussion of the prostaglandins, see Bergstrom, et al., Pharmacol. Rev. 20:1 (1968) and references cited therein. For a further discussion of the uses of the E-type prostaglandins, see, e.g., U.S. Pat. No. 3,966,962, and references cited therein.
The problem in formulating prostaglandin compounds of the E series is the lack of stability of the compounds. These compounds tend to decompose, especially at room temperature (25.degree. C.) and higher, and especially in the presence of small amounts of acid or base. Reasonable stability of prostaglandin compounds of the E series can be obtained by maintaining the temperature of the compound at -20.degree. C. or lower. However, storage under such temperature conditions is usually inconvenient when the compounds are being used for the pharmacological purposes referred to above. Some limited success has been achieved by dissolving the prostaglandin in solvents such as ethyl acetate, chloroform, and ethanol. See, e.g., U.S. Pat. Nos. 3,749,800; 3,826,823; 3,829,579; and 3,851,052. However, these solutions do not provide long-term stability at room temperature. Solutions of PGE compounds in ethanol, for example, are not stable above 4.degree. C.
Triacetin solutions are relatively stable at room temperature and higher. However, triacetin is very bitter tasting, making it unsuitable for oral administration alone. Much of the bitter taste of triacetin is removed by dissolving it in water. However, triacetin takes a relatively long time to dissolve in water (e.g., 60 seconds or more). Triacetin's poor water miscibility can thus result in incomplete doses of the drug being administered due to poor patient compliance (e.g., failure to dissolve the drug completely and the like).
Ethanol is instantly miscible with water, but, as noted above, solutions of PGE compounds in ethanol are unstable above 4.degree. C.
Thus, each of the prior art solvents has certain drawbacks for oral administration.